Background and Aims Perineural invasion (PNI) is one of the biological characteristics of local invasion and metastasis of gastric cancer, but its clinical value has not been paid much attention. The purpose of this study was to investigate clinicopathologic features in gastric cancer with PNI and the influence of PNI on prognosis of gastric cancer patients.Methods The clinicopathologic data of 543 patients with gastric cancer who underwent open radical gastrectomy were retrospectively analyzed. The patients were divided into PNI-positive group and PNI-negative group, and the differences in clinicopathologic variables between the two groups were compared. Propensity score matching was used to equalize the basic variables related to prognosis in the two groups. Survival analysis was conducted using Kaplan-Meier method and Cox proportional hazard model was used to analyze the risk factors associated with postoperative survival of PNI-positive gastric cancer patients.Results The positive rate of PNI in gastric cancer patients was 21.18% (115/543). Before matching, there were statistically significant differences in terms of tumor size, tumor site, degree of tumor cell differentiation, tumor TNM stage, presence of vascular invasion, surgical resection scope and postoperative adjuvant chemotherapy between the two groups (all P<0.05). After matching, 65 patients were allocated to PNI-positive group and 98 patients allocated to PNI-negative group, and the baseline clinicopathologic data of the two groups were well matched (all P>0.05). The overall survival time (OS) of PNI-positive group was significantly shorter than that of PNI-negative group (median OS: 19 months vs. 49 months, P=0.002); subgroup analysis showed that positive PNI exerted no significant influence on OS in TNM stage I-II patients (P=0.432), but significantly reduced the OS in stage III patients (median OS: 18 months vs. 2 months, P<0.001). In PNI-positive patients, postoperative adjuvant chemotherapy exerted no significant influence on OS in stage I-II patients (P=0.975), but significantly prolonged the OS in stage III patients (median OS: 18 months vs. 2 months, P<0.001). Univariate analysis demonstrated that age (P=0.008), tumor TNM stage (P=0.034), and absence of postoperative adjuvant chemotherapy (P=0.006) were significantly associated with the prognosis of patients with PNI-positive gastric cancer. Multivariable analysis revealed that TNM stage III (HR=2.591, 95% CI=1.291-5.198, P=0.007) and absence of postoperative adjuvant chemotherapy (HR=0.345, 95% CI=0.184-0.649, P=0.001) were independent risk factors for the prognosis of PNI-positive gastric cancer.Conclusion The prognosis of PNI-positive gastric cancer patients is poor than that of PNI-negative ones, which is particularly obvious in those with TNM stage III disease. Aggressive postoperative adjuvant chemotherapy may be helpful for improving the outcomes of these patients.